Cephem antibiotics have been widely used for the treatment of bacterial infections both in hospitals and in the general public. As such, it is highly desirable to use cephem antibiotics showing activity against both gram-positive and gram-negative bacteria. Unfortunately, due to the existence of multiple-drug resistant gram-negative and gram-positive organisms, many bacteria have become highly resistant to a number of β-lactam drugs, including the bacteria that constitute the ESKAPE organisms, generally encompassed by the following six pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species. This includes a resistance to known cephems whereby the bacteria are producing β-lactamases, including Class A (ESBL) and Class D (serine β-lactamases) types, which have an extended substrate spectrum. As a result, the morbidity and mortality caused by bacterial infections in both hospital and community settings continues to rise, and has become a significant public health concern.
There is a demand for development of new cephem compounds which exhibit more potent antimicrobial activity in particular more effective against a variety of β-lactamase producing gram-positive and gram-negative bacteria.
A variety of cephem compounds having a quaternary ammonium group at the 3-side chain and 2-(2-aminothiazol-4-yl)-2-hydroxy-(or substituted hydroxyl)aminoacetamido group at 7-position have been published such as, for example, U.S. Pat. Nos. 4,864,022, 5,173,485 ,5,215,982, 5,071,979, 4,406,899, 4,910,301, 4,748,171, 5,010,188, International Patent Application Nos. PCT/JP2003/013684, PCT/JP2007/056136, PCT/IB2013/002423, European Patent Application No. 2 703 406, European Patent Application No. 2 557 082; European Patent No. 2 341 053; European Patent Application No. 2 70606, United States Patent Application No. 2013/0079319 (Shionogi), United States Patent Application No. 2012/0264727, and European Patent Application No. 2706062.
The above mentioned patents and patent applications disclose cephem compounds whose quaternary ammoniomethyl group at the 3-position has a monocyclic or bicyclic nitrogen-containing heterocyclic or aromatic heterocyclic ring which is optionally substituted with an organic group other than benzamidine, heteroaryl amidine, arylguanidine and heteroaryl guanidine as the terminal residues.
There remains a need for new cephem compounds having increased antibiotic efficacy, particularly in highly resistant gram-positive and gram-negative bacteria, the compounds having structural features are significantly different from the compounds described in the patent references cited above